August 23, 2016
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Berinert

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Berinert




Side Effects
Interactions

SIDE EFFECTS

The most serious adverse reaction reported in subjects enrolled in clinical studies who received Berinert was an increase in the severity of pain associated with HAE.

The most common adverse reaction reported in greater than 4% of the subjects and greater than placebo among subjects who received Berinert in the placebo-controlled clinical trial was dysgeusia.

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Placebo-controlled Clinical Study

In the placebo-controlled clinical study, referred to as the randomized clinical trial (RCT) [see Clinical Studies], 124 subjects experiencing an acute moderate to severe abdominal or facial HAE attack were treated with Berinert (either a 10 IU per kg body weight or a 20 IU per kg body weight dose), or placebo (physiological saline solution). The treatment-emergent serious adverse reactions/events that occurred in 5 subjects in the RCT were laryngeal edema, facial attack with laryngeal edema, swelling (shoulder and chest), exacerbation of hereditary angioedema, and laryngospasm.

Table 1: Adverse Reactions* Occurring up to 4 Hours After Initial Infusion in More Than 4% of Subjects†

Adverse Reactions Number (%) of Subjects Reporting Adverse Reactions
Berinert 20 IU/kg
(n=43)
Number (%) of Subjects Reporting Adverse Reactions
Placebo Group
(n=42)
Nausea* 3 (7%) 5 (11.9%)
Dysgeusia 2 (4.7%) 0 (0)
Abdominal Paint 2 (4.7%) 3 (7.1%)
Vomitingt 1 (2.3%) 3 (7.1%)
Diarrheat 0 (0) 4 (9.5%)
Headache 0 (0) 2 (4.8%)
* Comprises adverse events that began within 4 hours of infusion; these events were considered adverse reactions irrespective of reported causality.
† The following abdominal symptoms were identified in the protocol as associated with HAE abdominal attacks: abdominal pain, bloating, cramps, nausea, vomiting, and diarrhea.

Table 2: Adverse Reactions* Occurring in More Than 4% of Subjects up to 72 Hours After Infusion of Initial or Rescue Medication† by Intentto- Treat

Adverse Reactions Number (%) of Subjects Reporting Adverse Reactions†‡ Berinert 20 IU/kg (n=43)
Number (%) of Subjects Reporting Adverse Reactions†‡ Placebo Group
(n=42)
Nausea 3 (7%) 11 (26.2%)
Headache 3 (7%) 5 (11.9%)
Abdominal Pain 3 (7%) 5 (11.9%)
Dysgeusia 2 (4.7%) 1 (2.4%)
Vomiting 1 (2.3%) 7 (16.7%)
Pain 1 (2.3%) 4 (9.5%)
Muscle spasms 1 (2.3%) 4 (9.5%)
Diarrhea 0 (0) 8 (19%)
Back pain 0 (0) 2 (4.8%)
Facial pain 0 (0) 2 (4.8%)
* Comprises adverse events that began within 72 hours of infusion; these events were considered adverse reactions irrespective of reported causality.
† If a subject experienced no relief or insufficient relief of symptoms within 4 hours after infusion, investigators had the option to administer a blinded second infusion (“rescue” treatment) of Berinert (20 IU/kg for the placebo group or 10 IU/kg for the 10 IU/kg group), or placebo (for the 20 IU/kg group).
‡ Adverse reactions following either initial treatment and/or blinded “rescue” treatment. Because more subjects in the placebo randomization group than in the Berinert randomization group received rescue treatment, the median observation period in this analysis for subjects randomized to placebo was slightly longer than for subjects randomized to receive Berinert.

Subjects were tested at baseline and after 3 months for possible exposure to Parvovirus B19, hepatitis B, hepatitis C, and HIV-1 and HIV-2. No subject who underwent testing evidenced seroconversion or treatment-emergent positive polymerase chain reaction testing for these pathogens.

Extension Study

In the safety analysis of the open-label extension study, 57 subjects with 1085 acute moderate to severe abdominal, facial, peripheral, and laryngeal attacks received a 20 IU/kg body weight dose of Berinert [see Clinical Studies]. This study provides additional safety data in subjects who received multiple infusions of the product for sequential HAE attacks (one infusion per attack).

Table 3 lists the adverse reactions that occurred in the safety analysis of the open-label extension study in ≥ 2 subjects or associated with ≥ 5 attacks during infusion or within 24 hours or 72 hours after the end of a Berinert infusion.

Table 3: Incidence of Subjects and Attacks with Adverse Reactions (ARs)* Starting during Infusion or Within 24 Hours or 72 Hours after End of an Infusion (Experienced by ≥ 2 Subjects or Associated with ≥ 5 Attacks Overall) by Preferred Term (Safety Subject and Attack Populations)

Preferred term Number (%) of Subjects
(n=57)
Number (%) of Attacks
(n=1085)
ARs within 24 hours ARs within 72 hours ARs within 24 hours ARs within 72 hours
Any preferred term 13 (22.8%) 20 (35.1%) 27 (2.5%) 41 (3.8%)
Headache 2 (3.5%) 4 (7.0%) 3 (0.3%) 6 (0.6%)
Nasopharyngitis 1 (1.8%) 2 (3.5%) 1 ( < 0.1%,) 2 (0.2%)
Abdominal pain or discomfort 1 (1.8%) 3 (5.3%) 2 (0.2%) 6 (0.6%)
Upper respiratory tract infection 0 (0) 1 (1.8%) 0 (0) 1 ( < 0.1%,)
Hereditary angioedema† 1 (1.8%) 1 (1.8%) 1 ( < 0.1%,) 1 ( < 0.1%,)
Influenza like illness 1 (1.8%) 2 (3.5%) 1 ( < 0.1%,) 2 (0.2%)
Rash 2 (3.5%) 2 (3.5%) 2 (0.2%) 2 (0.2%)
Vulvovaginal mycotic infection 0 (0) 2 (3.5%) 0 (0) 2 (0.2%)
Nausea 1 (1.8%) 1 (1.8%) 4 (0.4%) 5 (0.5%)
N = total number of subjects/attacks
Data are sorted by decreasing frequency by number of subjects.
* Because of the allowance of rescue medication in both study arms, all listed adverse events were considered to be at least potentially related to study medication (eg, adverse reactions), regardless of the investigator's opinion concerning causality.
† Hereditary angioedema attacks were only to be reported as adverse reaction if it was a worsening of symptoms during a treated attack. New attacks were not to be reported as adverse reactions. Although the adverse reaction of hereditary angioedema in subject 22301 was a new attack that started after the previous attack had completely resolved, this attack was reported as an adverse reaction, because the attack was not included in the study and treated outside study site with medication other than the study medication.

Table 4: Summary of Adverse Reactions* by Type of Attack (Safety Subject Population)

Overall ARs Type of Attack
Number (%) of Subjects
Abdominal
(n=51)
Peripheral
(n=30)
Laryngeal
(n=16)
Facial
(n=21)
Other
(n=3)
Subjects with ARs 17 (33.3%) 7 (23.3%) 2 (12.5%) 0 (0) 0 (0)
Subjects with serious ARs 1 (2.0%) 0 (0) 0 (0) 0 (0) 0 (0)
Study medication permanently discontinued due to ARs 1 (2.0%) 0 (0) 0 (0) 0 (0) 0 (0)
Most frequent ARs ( ≥ 3 subjects overall)
Headache 5 (9.8%) 0 (0) 0 (0) 0 (0) 0 (0)
Nasopharyngitis 1 (2.0%) 2 (6.7%) 0 (0) 0 (0) 0 (0)
Other ARs ( < 3 subjects overall)
Abdominal discomfort 0 (0) 1 (3.3%) 0 (0) 0 (0) 0 (0)
Dizziness 1 (2.0%) 0 (0) 0 (0) 0 (0) 0 (0)
Dry mouth 0 (0) 1 (3.3%) 0 (0) 0 (0) 0 (0)
Erythema infectiosum 1 (2.0%) 0 (0) 0 (0) 0 (0) 0 (0)
Headache 1 (2.0%) 0 (0) 0 (0) 0 (0) 0 (0)
Infusion-related reaction 1 (2.0%) 0 (0) 0 (0) 0 (0) 0 (0)
Influenza like illness 1 (2.0%) 0 (0) 1 (6.3%) 0 (0) 0 (0)
Pruritus 0 (0) 1 (3.3%) 0 (0) 0 (0) 0 (0)
Rash 0 (0) 1 (3.3%) 0 (0) 0 (0) 0 (0)
N = number of subjects
Only ARs associated with attacks of the respective subgroups were included in the analysis.
* Because of the allowance of rescue medication in both study arms, all listed adverse events were considered to be at least potentially related to study medication (eg, adverse reactions), regardless of the investigator's opinion concerning causality.

The incidence and type of adverse reactions with Berinert when administered for treatment of multiple consecutive acute HAE attacks of any type was similar to those previously observed. As in the placebo-controlled study, no proven cases of infections due to HIV-½, HAV, HBV, HCV or Parvovirus B19 were observed during the study.

Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

Adverse reactions reported in Europe since 1979 in patients receiving Berinert for treatment of HAE include hypersensitivity/anaphylactic reactions, injection-site pain, injection-site redness, chills, and fever.

TE Events Associated With HAE Treatment

TE events including basilar artery thrombosis, multiple pulmonary microemboli, and thrombosis have been reported with the use of Berinert at the recommended dose following treatment of HAE.

TE Events Associated With Use In Unapproved Indications

TE events have also been reported with the use of Berinert in patients receiving higher than recommended doses during cardiac surgery (unapproved indication) include carotid artery thrombosis, cerebral thrombosis, myocardial infarction, pulmonary embolism, renal vein thrombosis, sagittal sinus thrombosis, inferior vena cava thrombosis, superior vena cava thrombosis, internal jugular vein thrombosis, and peripheral venous thrombosis.1 The following adverse reactions, identified by system organ class, have been attributed to Berinert during post-approval use outside the US.

  • Immune System Disorder: Hypersensitivity/anaphylactic reactions, and shock
  • General/Body as a Whole: Pain on injection, redness at injection site, chills, and fever

Read the Berinert ([c1 esterase inhibitor (human)] freeze-dried powder) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No drug interaction studies have been conducted.

Read the Berinert Drug Interactions Center for a complete guide to possible interactions

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 6/16/2016

Side Effects
Interactions

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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